AVANDAMET (rosiglitazone maleate 4 mg metformin hydrochloride 1000 mg) Dailymed

5 Warnings And Precautions

• Fluid retention, which may exacerbate or lead to heart failure, may occur. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk of other cardiovascular effects. (5.2)
• Increased risk of myocardial infarction has been observed in a meta-analysis of 52 clinical trials of rosiglitazone (incidence rate 0.4% versus 0.3%). (5.3)
• Coadministration with insulin is not recommended. (1, 5.2, 5.3)
• Assess renal function before starting therapy and at least annually. (5.1)
• Avoid use in patients with evidence of hepatic disease. (2.4, 5.1)
• Warn patients against excessive alcohol intake. (5.1)
• Promptly evaluate patients who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis. (5.1)
• Dose-related edema (5.4), weight gain (5.5), and anemia (5.9) may occur.
• Macular edema has been reported. (5.7)
• Increased incidence of bone fracture. (5.8)
• Measure hematologic parameters annually. (5.9)

5.1 Lactic Acidosis

Incidence and Management: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with AVANDAMET; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1,000 patient years of exposure, with approximately 0.015 fatal cases/1,000 patient years of exposure). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking AVANDAMET and by use of the minimum effective dose of AVANDAMET. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Treatment with AVANDAMET should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, AVANDAMET should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, AVANDAMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking AVANDAMET, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, AVANDAMET should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. AVANDAMET should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of AVANDAMET, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking AVANDAMET do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling.

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking AVANDAMET, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications (4)].

Factors That May Predispose Patients to Lactic Acidosis: Assessment of Renal Function: Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive AVANDAMET. In patients with advanced age, AVANDAMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. [See Dosage and Administration (2.4) and Use in Specific Populations (8.5).]

Before initiation of therapy with AVANDAMET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and AVANDAMET discontinued if evidence of renal impairment is present.

Medications That Affect Renal Function: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.2) and Clinical Pharmacology (12.4)], should be used with caution.

Hypoxic States: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving AVANDAMET, the drug should be promptly discontinued.

Radiologic Studies With Intravascular Iodinated Contrast Materials: Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications (4)]. Therefore, in patients in whom any such study is planned, AVANDAMET should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Surgical Procedures: Use of AVANDAMET should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving AVANDAMET.

Change in Clinical Status of Patients With Previously Controlled Diabetes: A patient with type 2 diabetes previously well-controlled on AVANDAMET who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, AVANDAMET must be stopped immediately and other appropriate corrective measures initiated.

[See also Warnings and Precautions (5.6).]

5.2 Cardiac Failure

Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered [see Boxed Warning].

Patients with congestive heart failure (CHF) NYHA Class I and II treated with rosiglitazone have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled echocardiographic trial was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed with rosiglitazone treatment compared to placebo during the 52-week trial. (See Table 2.)

Table 2. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With Rosiglitazone or Placebo (in Addition to Background Antidiabetic and CHF Therapy)

Events	Rosiglitazone	Placebo
	N = 110 n (%)	N = 114 n (%)
Adjudicated
Cardiovascular deaths	5 (5%)	4 (4%)
CHF worsening	7 (6%)	4 (4%)
– with overnight hospitalization	5 (5%)	4 (4%)
– without overnight hospitalization	2 (2%)	0 (0%)
New or worsening edema	28 (25%)	10 (9%)
New or worsening dyspnea	29 (26%)	19 (17%)
Increases in CHF medication	36 (33%)	20 (18%)
Cardiovascular hospitalizationa	21 (19%)	15 (13%)
Investigator-reported, non-adjudicated
Ischemic adverse events	10 (9%)	5 (4%)
– Myocardial infarction	5 (5%)	2 (2%)
– Angina	6 (5%)	3 (3%)

^aIncludes hospitalization for any cardiovascular reason.

Initiation of AVANDAMET in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDAMET is not recommended in patients with symptomatic heart failure. [See Boxed Warning.]

Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of AVANDAMET is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDAMET during this acute phase should be considered.

Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. AVANDAMET is not recommended in patients with NYHA Class III and IV cardiac status.

Congestive Heart Failure During Coadministration of Rosiglitazone With Insulin:In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure. Coadministration of rosiglitazone and insulin is not recommended. [See Indications and Usage (1) and Warnings and Precautions (5.3).]

In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis¹ [see Warnings and Precautions (5.3)], patients with type 2 diabetes mellitus were randomized to coadministration of rosiglitazone and insulin (N = 1,018) or insulin (N = 815). In these 7 trials, rosiglitazone was added to insulin. These trials included patients with long-standing diabetes (median duration of 12 years) and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. The total number of patients with emergent congestive heart failure was 23 (2.3%) and 8 (1.0%) in the rosiglitazone plus insulin and insulin groups, respectively.

Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing Rosiglitazone to Pioglitazone: Three observational studies^2-4 in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of hospitalized heart failure compared to use of pioglitazone. One other observational study⁵ in patients with a mean age of 54 years, which also included an analysis in a subpopulation of patients >65 years of age, found no statistically significant increase in emergency department visits or hospitalization for heart failure in patients treated with rosiglitazone compared to pioglitazone in the older subgroup.

5.3 Major Adverse Cardiovascular Events

Cardiovascular adverse events have been evaluated in a meta-analysis of 52 clinical trials, in long-term, prospective, randomized, controlled trials, and in observational studies.

Meta-Analysis of Major Adverse Cardiovascular Events in a Group of 52 Clinical Trials: A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 52 double-blind, randomized, controlled clinical trials (mean duration 6 months).¹ These trials had been conducted to assess glucose-lowering efficacy in type 2 diabetes. Prospectively planned adjudication of cardiovascular events did not occur in most of the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled trials included monotherapy trials (monotherapy with rosiglitazone versus placebo monotherapy) and add-on trials (rosiglitazone or placebo, added to sulfonylurea, metformin, or insulin). Active control trials included monotherapy trials (monotherapy with rosiglitazone versus sulfonylurea or metformin monotherapy) and add-on trials (rosiglitazone plus sulfonylurea or rosiglitazone plus metformin, versus sulfonylurea plus metformin). A total of 16,995 patients were included (10,039 in treatment groups containing rosiglitazone, 6,956 in comparator groups), with 5,167 patient-years of exposure to rosiglitazone and 3,637 patient-years of exposure to comparator. Cardiovascular events occurred more frequently for patients who received rosiglitazone than for patients who received comparators (see Table 3).

Table 3. Occurrence of Cardiovascular Events in a Meta-Analysis of 52 Clinical Trials

Eventa	Rosiglitazone (N=10,039) n (%)	Comparator (N=6,956) n (%)
MACE (a composite of myocardial infarction, cardiovascular death, or stroke)	70 (0.7)	39 (0.6)
Myocardial Infarction	45 (0.4)	20 (0.3)
Cardiovascular Death	17 (0.2)	9 (0.1)
Stroke	18 (0.2)	16 (0.2)
All-cause Death	29 (0.3)	17 (0.2)

^a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

In this analysis, a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed. Analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death), referred to hereafter as MACE. Rosiglitazone had a statistically non-significant increased risk of MACE compared to the pooled comparators. A statistically significant increased risk of myocardial infarction and statistically non-significant increased risk of MACE with rosiglitazone was observed in the placebo-controlled trials. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. (See Figure 1 and Table 4.)
Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for MACE and Myocardial Infarction in the Meta-Analysis of 52 Clinical Trials

Table 4. Occurrence of MACE and Myocardial Infarction in a Meta-Analysis of 52 Clinical Trials by Trial Type

			MACE		Myocardial Infarction
		N	n (%)	OR (95%CI)	n (%)	OR (95%CI)
Active- Controlled Trials	RSG	2,119	16 (0.8%)	1.05	10 (0.5%)	1.00
	Control	1,918	14 (0.7%)	(0.48, 2.34)	9 (0.5%)	(0.36, 2.82)
Placebo- Controlled Trials	RSG	8,124	54 (0.7%)	1.53	35 (0.4%)	2.23
	Placebo	5,636	28 (0.5%)	(0.94, 2.54)	13 (0.2%)	(1.14, 4.64)
Overall	RSG	10,039	70 (0.7%)	1.44	45 (0.4%)	1.8
	Control	6,956	39 (0.6%)	(0.95, 2.20)	20 (0.3%)	(1.03, 3.25)

RSG = rosiglitazone

Of the placebo-controlled trials in the meta-analysis, 7 trials had patients randomized to rosiglitazone plus insulin or insulin. There were more patients in the rosiglitazone plus insulin group compared to the insulin group with myocardial infarctions, MACE, cardiovascular deaths, and all-cause deaths (see Table 5). The total number of patients with stroke was 5 (0.5%) and 4 (0.5%) in the rosiglitazone plus insulin and insulin groups, respectively. The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction [See Warnings and Precautions (5.1).]

Table 5. Occurrence of Cardiovascular Events for Rosiglitazone in Combination With Insulin in a Meta-Analysis of 52 Clinical Trials

Eventa	Rosiglitazone (N=1,018) (%)	Insulin (N = 815) (%)	OR (95% CI)
MACE (a composite of myocardial infarction, cardiovascular death, or stroke)	1.3	0.6	2.14 (0.70, 7.83)
Myocardial infarction	0.6	0.1	5.6 (0.67, 262.7)
Cardiovascular death	0.4	0.0	ND, (0.47, ∞)
All cause death	0.6	0.2	2.19 (0.38, 22.61)

ND = not defined

^a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

Myocardial Infarction Events in Large, Long-Term, Prospective, Randomized, Controlled Trials of Rosiglitazone: Data from 3 large, long-term, prospective, randomized, controlled clinical trials of rosiglitazone were assessed separately from the meta-analysis.^6-8 These 3 trials included a total of 14,067 patients (treatment groups containing rosiglitazone N = 6,311; comparator groups N = 7,756), with patient-year exposure of 24,534 patient-years for rosiglitazone and 28,882 patient-years for comparator. Patient populations in the trials included patients with impaired glucose tolerance, patients with type 2 diabetes who were initiating oral agent monotherapy, and patients with type 2 diabetes who had failed monotherapy and were initiating dual oral agent therapy. Duration of follow-up exceeded 3 years in each trial.

In each of these trials, there was a statistically non-significant increase in the risk of myocardial infarction for rosiglitazone versus comparator medications.

In a long-term, randomized, placebo-controlled, 2x2 factorial trial intended to evaluate rosiglitazone, and separately ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes in 5,269 subjects with glucose intolerance, the incidence of myocardial infarction was higher in the subset of subjects who received rosiglitazone in combination with ramipril than among subjects who received ramipril alone but not in the subset of subjects who received rosiglitazone alone compared to placebo.⁶ The higher incidence of myocardial infarction among subjects who received rosiglitazone in combination with ramipril was not confirmed in the two other large (total N = 8,798) long-term, randomized, active-controlled clinical trials conducted in patients with type 2 diabetes, in which 30% and 40% of patients in the two trials reported angiotensin-converting enzyme inhibitor use at baseline.^7,8

There have been no adequately designed clinical trials directly comparing rosiglitazone to pioglitazone on cardiovascular risks. However, in a long-term, randomized, placebo-controlled cardiovascular outcomes trial comparing pioglitazone to placebo in patients with type 2 diabetes mellitus and prior macrovascular disease, pioglitazone was not associated with an increased risk of myocardial infarction or total mortality.⁹

The increased risk of myocardial infarction observed in the meta-analysis and large, long-term controlled clinical trials, and the increased risk of MACE observed in the meta-analysis described above, have not translated into a consistent finding of excess mortality from controlled clinical trials or observational studies. Clinical trials have not shown any difference between rosiglitazone and comparator medications in overall mortality or CV-related mortality.

Mortality in Observational Studies of Rosiglitazone Compared to Pioglitazone: Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of all-cause mortality compared to use of pioglitazone.^2-4 One observational study⁵ in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with rosiglitazone compared to pioglitazone and reported similar results in the subpopulation of patients >65 years of age. One additional small, prospective, observational study¹⁰ found no statistically significant differences for CV mortality and all-cause mortality in patients treated with rosiglitazone compared to pioglitazone.

5.4 Edema

AVANDAMET should be used with caution in patients with edema. In a clinical trial in healthy volunteers who received rosiglitazone 8 mg once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo. Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, AVANDAMET should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see Boxed Warning, Warnings and Precautions (5.2), and Patient Counseling Information (17.1)].

In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with rosiglitazone, and may be dose-related. Patients with ongoing edema were more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone [see Adverse Reactions (6.1)]. The use of AVANDAMET in combination with insulin is not recommended. [See Warnings and Precautions (5.2, 5.3).]

5.5 Weight Gain

Dose-related weight gain was seen with rosiglitazone alone and rosiglitazone together with other hypoglycemic agents (see Table 6). No overall change in median weight was observed with AVANDAMET in drug-naïve patients. The mechanism of weight gain with rosiglitazone is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 6. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials [Median (25^th, 75^th, Percentile)]

Monotherapy
Duration	Control Group		Rosiglitazone 4 mg	Rosiglitazone 8 mg
26 weeks	Placebo	-0.9 (-2.8, 0.9) N = 210	1.0 (0.9, 3.6) N = 436	3.1 (1.1, 5.8) N = 439
52 weeks	Sulfonylurea	2.0 (0, 4.0) N = 173	2.0 (-0.6, 4.0) N = 150	2.6 (0, 5.3) N = 157
Combination Therapy
				Rosiglitazone + Control Therapy
Duration	Control Group		Rosiglitazone 4 mg	Rosiglitazone 8 mg
24-26 weeks	Sulfonylurea	0 (-1.0, 1.3) N = 1,155	2.2 (0.5, 4.0) N = 613	3.5 (1.4, 5.9) N = 841
26 weeks	Metformin	-1.4 (-3.2, 0.2) N = 175	0.8 (-1.0, 2.6) N = 100	2.1 (0, 4.3) N = 184
26 weeks	Insulin	0.9 (-0.5, 2.7) N = 162	4.1 (1.4, 6.3) N = 164	5.4 (3.4, 7.3) N = 150
AVANDAMET + Insulin
Duration	Control Group			AVANDAMET + Insulin
24 weeks	Insulin	2.6 kg (0.3, 4.8) N = 145		3.3 kg (1.5, 6.0) N = 147

In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication, the median weight change (25^th, 75^th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for rosiglitazone, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.

In postmarketing experience with rosiglitazone alone or in combination with other hypoglycemic agents, there have been rare reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning].

5.6 Hepatic Effects

Metformin: Since impaired hepatic function has been associated with some cases of lactic acidosis, AVANDAMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Rosiglitazone: Liver enzymes should be measured prior to the initiation of therapy with AVANDAMET in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with AVANDAMET should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤2.5X upper limit of normal) at baseline or during therapy with AVANDAMET should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with AVANDAMET in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with AVANDAMET, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with AVANDAMET should be discontinued.

If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with AVANDAMET should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

In addition, if the presence of hepatic disease or hepatic dysfunction of sufficient magnitude to predispose to lactic acidosis is confirmed, therapy with AVANDAMET should be discontinued.

5.7 Macular Edema

Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient’s underlying medications or other physical findings. [See Adverse Reactions (6.3).]

5.8 Fractures

In a 4- to 6-year comparative trial (ADOPT) of glycemic control with monotherapy in drug-naïve patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking rosiglitazone. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for rosiglitazone versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the trial. The majority of the fractures in the women who received rosiglitazone occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). Other trials suggest that this risk may also apply to men, although the risk of fracture among women appears higher than that among men. The risk of fracture should be considered in the care of patients treated with rosiglitazone, and attention given to assessing and maintaining bone health according to current standards of care.

5.9 Hematologic Effects

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone [see Adverse Reactions (6.2)]. The observed changes may be related to the increased plasma volume observed with treatment with rosiglitazone and may be dose-related. The decrease in hemoglobin was seen more frequently in combination rosiglitazone and metformin therapy than in rosiglitazone therapy alone. Vitamin B₁₂ deficiency may contribute to the observed reductions in hemoglobin [see Warnings and Precautions (5.10)]. Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) should be performed, at least on an annual basis.

5.10 Vitamin B12 Levels

In controlled clinical trials of metformin of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. In these patients, routine serum vitamin B₁₂ measurements at 2- to 3-year intervals may be useful. Vitamin B₁₂ deficiency should be excluded if megaloblastic anemia is suspected. [See Warnings and Precautions (5.9).]

5.11 Diabetes and Blood Glucose Control

Periodic fasting blood glucose and HbA1c measurements should be performed to monitor therapeutic response.

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold AVANDAMET and temporarily administer insulin. AVANDAMET may be reinstituted after the acute episode is resolved.

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with hypoglycemic agents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic blocking drugs.

Patients receiving rosiglitazone in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

5.12 Ovulation

Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking AVANDAMET [see Use in Specific Populations (8.1)]. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials; therefore, the frequency of this occurrence is not known.

Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology (13.1)], the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDAMET should be reviewed.